Endothelin-1-induced in vitro cerebral venoconstriction is mediated by endothelin ETA receptors

Fernández, Núria; Monge, Luis; Garcı́a-Villalón, Ángel Luis; Garcia, J. L.; Gómez, B.; Diéguez, Godofredo

doi:10.1016/0014-2999(95)00577-3

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…We considered the possibility that blockade of NOS could simply be potentiating the vasoconstrictor effects of newly formed ET‐1 by inhibiting the NO produced following autocrine activation of ET B receptors (Warner et al ., 1989). However, NOS blockade failed to potentiate the vasoconstrictor effects of ET‐1, which is consistent with other studies (Fernandez et al ., 1995; Ferrero et al ., 2008), suggesting that NO derived from ET B activation does not appreciably oppose vasoconstriction. In this regard, it is tempting to further speculate that autocrine activation of ET B receptors in vivo produces low quantities of NO that are sufficient to inhibit further ET‐1 production, but do not contribute directly to modulation of vascular tone.…”

Section: Discussionsupporting

confidence: 93%

Role of endothelin‐1 in the hyper‐responsiveness to nitrovasodilators following acute NOS inhibition

Bourque

Whittingham

Brien

et al. 2012

British J Pharmacology

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BACKGROUND AND PURPOSE Acute NOS inhibition in humans and animals is associated with hypersensitivity to NO donors. The mechanisms underlying this phenomenon have not been fully elucidated. The purpose of the present study was to assess whether hypersensitivity to NOS‐blockade is linked to endothelin‐1 (ET‐1) signalling. EXPERIMENTAL APPROACH Sprague Dawley rats were instrumented with indwelling arterial and venous catheters for continuous assessments of haemodynamic parameters and drug delivery, respectively. Mesenteric arteries were isolated and tested for reactivity by wire myography. KEY RESULTS NOS blockade with L‐NG‐nitroarginine methyl ester (L‐NAME) caused a pronounced increase in arterial blood pressure (BP) (∼40 mmHg). In L‐NAME‐treated animals, the dose of sodium nitroprusside (SNP) required to cause a significant reduction in arterial BP was lower than in vehicle‐treated rats (P < 0.001), and the magnitude of the reduction in BP was greater. Similar results were obtained with other NO mimetics, but not isoprenaline; moreover, decreasing the BP back to baseline levels with prazosin after L‐NAME treatment did not attenuate the hyper‐responsiveness to NO donors. The increased responsiveness to NO donors was abolished by pretreatment with the ETA/B receptor antagonist, PD145065, or the ETA receptor‐specific antagonist ABT627. Ex vivo, L‐NAME treatment potentiated the constriction induced by big endothelin‐1 (bET‐1), the precursor to active ET‐1, but had no effect on the ET‐1‐mediated constriction. CONCLUSIONS AND IMPLICATIONS These data suggest that the increased sensitivity to NO donors is mediated, at least in part, by ET‐1 in vivo, and the mechanism may involve the conversion of bET‐1 to ET‐1.

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Section: Discussionsupporting

confidence: 93%

Role of endothelin‐1 in the hyper‐responsiveness to nitrovasodilators following acute NOS inhibition

Bourque

Whittingham

Brien

et al. 2012

British J Pharmacology

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“…This mixed receptor population has been reported for the rabbit saphenous vein (Douglas et al ., 1995; Sudjarwo & Karaki, 1995), rabbit portal vein (Wang et al ., 1997), rabbit jugular vein and human saphenous vein (Wang et al ., 1997). There are exceptions such as the dog pial vein in which the predominant receptor appears to be the ET A receptor (Fernandez et al ., 1995). Presumably, ET B receptors are present in both smooth muscle and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists

Watts

Fink

Northcott

et al. 2002

British J Pharmacology

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1 Deoxycorticosterone acetate (DOCA) salt hypertension is associated with an endothelin-1 (ET-1)-dependent increase in arterial resistance and mean circulatory ®lling pressure. Contraction of endothelium-intact arteries and veins from sham and DOCA-salt hypertensive rats to agonists of the ET A (ET-1 (1 ± 31) ) and ET B receptor (sarafotoxin 6c; S6c) was investigated in tissue baths as was expression of mRNA for ET-1 and mRNA and protein for the ET A and ET B receptor. 2 ET-1 (1 ± 31) contracted aorta and vena cava from sham rats with a 30 fold lower potency than ET-1. Contraction was not altered by the ET B receptor antagonist BQ788 (100 nM) but was abolished by the ET A receptor antagonist ABT-627 (30 nM). 3 In DOCA-salt thoracic aorta, maximum contraction to ET-1 and ET-1 (1 ± 31) was reduced (36.6+6.3 and 13.3+4.4% of sham response, respectively); aorta did not contract to S6c. 4 In vena cava from DOCA-salt rats, contraction to ET-1 and ET-1 (1 ± 31) was not reduced compared to sham contraction; vena cava from sham and DOCA-salt rats contracted to S6c with a similar potency. 5 Real time RT ± PCR revealed that prepro ET-1 mRNA was increased 6.6+3.3 fold and 8.7+3.9 fold greater in DOCA-salt aorta and vena cava, respectively, compared to sham. Vena cava expressed a higher content of ET A and ET B receptor mRNA than aorta (P50.05), but no dierences were observed between sham and DOCA-salt tissues. ET A and ET B receptor protein was identi®ed in all tissues. Immunoreactive ET A receptor, observed as a 65, 30 and 28 kDa bands, was expressed 400% greater in DOCA-salt aorta compared to sham, but was not altered in vena cava. Immunoreactive ET B receptor, observed as 120, 45 and 30 kDa bands, tended to be higher in vena cava compared to aorta, but was not dierent in sham and DOCA-salt vena cava. 6 These results suggest that ET A receptor function is impaired in aorta but not vena cava of DOCA-salt rats. The ET B receptor was present in the aorta but, unlike in veins, does not mediate contraction directly. A sustained response to ET-1 in the venous circulation may contribute to the elevated blood pressure in the DOCA-salt model.

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“…ET-1 leads to vasoconstriction, by activating ETAR, which is expressed in endothelial cells (6,12,24), indicating that the effects of ET-1 on BMECs are mainly mediated by ETAR. ETAR antagonists can compete against ET-1 to bind specifically to ETAR and block the biological interaction between ET-1 and ETAR.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of endothelin A receptor protects brain microvascular endothelial cells against hypoxia-induced injury

Liu

Deng

et al. 2014

International Journal of Molecular Medicine

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Endothelin-1 (ET-1)-induced cell damage is commonly involved in ischemia/hypoxia-associated diseases. PD155080 [sodium 2-benzo (1.3)dioxol-5-yl-3-benzyl-4-(4‑metho-xyphenyl)-4-oxobut-2-enoate] is a selective endothelin A receptor (ETAR) antagonist that inhibits ET-1‑induced cell damage. The aim of this study was to investigate the effects of PD155080 on hypoxia-induced rat brain microvascular endothelial cell (BMEC) injury. BMECs were isolated from the cerebral cortex of Wistar rats and cultured in an anoxia chamber, containing 95% N(2) and 5% CO(2) for 12 h. BMEC injury was assessed by determining cellular ultra-microstructural changes and cell viability by MTT assay, trypan blue (TB) staining and measuring the lactate dehydrogenase (LDH) levels. ET-1 mRNA expression was detected by in situ hybridization and reverse transcription PCR (RT-PCR); the ET-1 protein level was measured by radioimmunoassay. Following exposure to hypoxic conditions, the viability of the BMECs was markedly decreased and the ultrastructure of the BMECs was damaged, as demonstrated by chromatin margination, chromatin agglutination, plasma edema, the increased number of intracellular liposomes and vacuoles, mitochondrial swelling and the expansion of a rough surfaced endoplasmic reticulum. The levels of ET-1 and ET-1 mRNA expression in the BMECs were increased following exposure to hypoxic conditions. Of note, the administration of PD155080 greatly enhanced the viability of the BMECs and ameliorated hypoxia-induced cellular injury. PD155080 also inhibited hypoxia-induced ET-1 production by the BMECs. In conclusion, PD155080 exerts protective effects against hypoxia-induced BMEC injury.

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Endothelin-1-induced in vitro cerebral venoconstriction is mediated by endothelin ETA receptors

Cited by 6 publications

References 34 publications

Role of endothelin‐1 in the hyper‐responsiveness to nitrovasodilators following acute NOS inhibition

Role of endothelin‐1 in the hyper‐responsiveness to nitrovasodilators following acute NOS inhibition

Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists

Inhibition of endothelin A receptor protects brain microvascular endothelial cells against hypoxia-induced injury

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